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Background/Objectives: Traumatic spinal cord injury (TSCI) profoundly impacts patients by precipitating a loss of motor and sensory capabilities, largely due to oxidative stress and inflammation during the secondary injury phase. Methods: This investigation explores the diagnostic potential of zinc (Zn) and free zinc (fZn) as biomarkers by analyzing their serum concentration dynamics in 48 TSCI individuals with TSCI, with the aim of correlating these levels with neurological impairment. Serum samples collected at admission, 4 h, 9 h, 12 h, 24 h, and 3 days post-injury were analyzed for total serum Zn and fZn concentrations. The patients were compared to a control group comprised of individuals with vertebral fractures but no neurological deficits. Results: The study revealed injury-specific fluctuations in Zn and fZn levels following TSCI, with significantly lower Zn levels observed post-TSCI compared to controls ( p = 0.016). The American Spinal Injury Association (ASIA) Impairment scale (AIS) assessments at admission and three months post-injury showed Zn level differences are linked to neurological recovery (AIS+:1 > AIS+:2, 0 h: p = 0.008; AIS+:0 < AIS+:1, 4 h: p = 0.016), highlighting the critical role of Zn and trace elements in the early remission process after TSCI. Notably, significant differences in fZn levels were detected between the control and TSCI groups (TSCI < Control; 12 h: p = 0.045; 24 h: p = 0.001; 3 d: p = 0.016), with the peak diagnostic performance of fZn at 24 h post-injury, as indicated by an Area Under the ROC Curve (AUC) of 83.84% (CI: 0.698-0.978). Conclusions: These findings underscore the potential of fZn as a biomarker to guide early diagnostic and therapeutic interventions aimed at mitigating secondary injury and enhancing recovery outcomes. This study contributes insights into the dynamics of serum Zn and its importance, holding specific diagnostic properties that could be critically relevant in the early phase of biomarker signature development for TSCI diagnostics and prognosis.

The thyroid hormone (TH) status is routinely assessed by thyrotropin (TSH) and thyroxine (T4). Both biomarkers are mainly regulated by TH receptor beta, whereas many peripheral organs employ the alpha receptor. Serum cluster of differentiation 5-like molecule (CD5L) is a liver-derived protein under control of both TH receptor isoforms. However, clinical data on its relation to TH status are sparse. An additional biomarker of TH status is needed in particular during pregnancy, where the routine biomarkers become dynamically disturbed. This study aimed to determine possible covariates regulating serum CD5L and to test its potential suitability as additional TH biomarker during pregnancy. A sandwich ELISA for serum CD5L was established using newly raised antibodies. Circadian effects and the impact of liver disease on serum CD5L concentrations were assessed. Serum samples from pregnant women with well-characterized TH and trace element status were analyzed, and CD5L concentrations were correlated with other indicators of TH status including TSH, fT4, fT3, copper, and selenium concentrations. The new quantitative assay for CD5L showed high accuracy. Serum CD5L was stable in dilution and refreezing experiments and did not show strong circadian variance or dependency on liver disease. In serum of pregnant women, CD5L correlated positively to fT3, but not to fT4 or TSH. Significant positive correlations of CD5L were observed with serum levels of the TH-responsive trace elements selenium and copper. The data support the potential suitability of serum CD5L as an additional marker of TH status, with potential value for pregnancy and thyroid disease., (© 2024 The Author(s). BioFactors published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)

Low-selenium status was associated with impaired renal function, which improved after selenium and coenzyme Q 10 supplementation in an RCT. Here, we evaluated serum glutathione peroxidase-3 (GPx3) and its relation to serum selenium, selenoprotein P (SELENOP), renal function, mortality, and the impact of supplementation, which are all important, especially in elderly individuals. In total, 383 study participants (197 receiving selenium yeast and coenzyme Q 10 and 186 on a placebo) were evaluated. We applied benchmark dose modelling to determine GPx3 saturation, ANCOVA, Kaplan-Meier, and multivariate Cox proportional regression analyses for mortality evaluations. Selenium and GPx3 activity were modestly correlated. In comparison with SELENOP, GPx3 levelled off at a much lower value, 100 vs. 150 µg Se/L. GPx3 was associated with renal function, but not SELENOP. Supplementation increased glomerular function by ≈23% with an increase in GPx3. Being low in GPx3 displayed twice the risks of mortality in both placebos and active treatments. At serum selenium <100 µg/L, GPx3 activity was dependent on both selenium status and renal function. As renal function is reduced in the elderly, GPx3 is not an appropriate marker of selenium status. Low GPx3 was associated with an increased risk of mortality dependent of selenium status and independent of renal function.

Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and begins with the uptake of the Sec carrier, selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP is metabolized via selenocysteine lyase (SCLY), producing selenide, a substrate for selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor, selenophosphate (H 2 SePO 3 - ), for the biosynthesis of the Sec-tRNA. Here, we discovered an alternative pathway in Sec metabolism mediated by peroxiredoxin 6 (PRDX6), independent of SCLY. Mechanistically, we demonstrate that PRDX6 can readily react with selenide and interact with SEPHS2, potentially acting as a selenium delivery system. Moreover, we demonstrate the functional significance of this alternative route in human cancer cells, revealing a notable association between elevated expression of PRDX6 and human MYCN-amplified neuroblastoma subtype. Our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering further possibilities for therapeutic exploitation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Selenium has potential safeguarding properties against cognitive decline, because of its role in protecting DNA, proteins, and lipids in the brain from oxidative damage. However, acute and chronic overexposure to selenium can be neurotoxic., Objective: The aim of this analysis was to explore the association between selenium status [serum selenium and selenoprotein P (SELENOP) concentrations and glutathione peroxidase 3 (GPx3) activity] and cognitive function in 85-y olds living in Northeast England at baseline and ≤5 y of follow-up., Methods: Global cognitive performance was assessed in 755 participants from the Newcastle 85+ study using the standardized Mini-Mental State Examination and attention-specific cognition was assessed using composite scores derived from the Cognitive Drug Research System. Serum selenium, SELENOP, and GPx3 activity were measured at baseline by total reflection X-ray fluorescence, enzyme-linked immunosorbent assay, and coupled-enzyme reaction, respectively. Regression analyses explored linear and nonlinear associations between continuous values and tertiles of selenium status biomarkers, respectively, and cognitive function at baseline. Generalized linear mixed models explored associations between continuous values and tertiles of selenium status biomarkers, and global cognitive decline over 5 y, and attention-specific cognitive decline over 3 y., Results: Over 3 and 5 y, none of the selenium biomarkers were associated with the rate of cognitive decline. At baseline, in fully adjusted models, higher serum selenium was nonlinearly associated with global cognition (β = 0.05 ± 0.01, P = 0.387 linear, β = 0.04 ± 0.01, P = 0.002 nonlinear). SELENOP and GPx3 activity were not associated with any cognitive outcomes., Conclusions: There were no associations between selenium status and cognitive decline. However, serum selenium, but not SELENOP or GPx3 activity, was positively associated nonlinearly with global cognition at baseline. Furthermore, these associations were not evident during follow-up, potentially because of residual confounding and reverse causation., Competing Interests: Conflict of interest LS holds shares on selenOmed GmbH, a company involved in selenium status assessment. All other authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Selenium (Se) is an essential trace element, which is inserted as selenocysteine (Sec) into selenoproteins during biosynthesis, orchestrating their expression and activity. Se is associated with both beneficial and detrimental health effects; deficient supply or uncontrolled supplementation raises concerns. In particular, Se was associated with an increased incidence of type 2 diabetes (T2D) in a secondary analysis of a randomized controlled trial (RCT). In this review, we discuss the intricate relationship between Se and diabetes and the limitations of the available clinical and experimental studies. Recent evidence points to sexual dimorphism and an association of Se deficiency with gestational diabetes mellitus (GDM). We highlight the emerging evidence linking high Se status with improved prognosis in patients with T2D and lower risk of macrovascular complications., Competing Interests: Declaration of interests L.S. hold shares of selenOmed GmbH, a company involved in Se status assessment; no other relationships or activities could appear to have influenced the submitted work. All other authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The liver-derived selenium (Se) transporter selenoprotein P (SELENOP) declines in critical illness as a negative acute phase reactant and has recently been identified as an autoantigen. Hepatic selenoprotein biosynthesis and cotranslational selenocysteine insertion are sensitive to inflammation, therapeutic drugs, Se deficiency, and other modifiers. As severe burn injury induces a heavy inflammatory burden with concomitant Se depletion, we hypothesized an impairment of selenoprotein biosynthesis in the acute post-burn phase, potentially triggering the development of autoantibodies to SELENOP (SELENOP-aAb). To test this hypothesis, longitudinal serum samples from severely burned patients were analyzed over a period of six months. Newly occurring SELENOP-aAb were detected in 8.4% (7/83) of the burn patients, with onset not earlier than two weeks after injury. Prevalence of SELENOP-aAb was associated with injury severity, as aAb-positive patients have suffered more severe burns than their aAb-negative counterparts (median [IQR] ABSI: 11 [7-12] vs. 7 [5.8-8], p = 0.023). Autoimmunity to SELENOP was not associated with differences in total serum Se or SELENOP concentrations. A positive correlation of kidney-derived glutathione peroxidase (GPx3) with serum SELENOP was not present in the patients with SELENOP-aAb, who showed delayed normalization of GPx3 activity post-burn. Overall, the data suggest that SELENOP-aAb emerge after severe injury in a subset of patients and have antagonistic effects on Se transport. The nature of burn injury as a sudden event allowed a time-resolved analysis of a direct trigger for new-onset SELENOP-aAb, which may be relevant for severely affected patients requiring intensified acute and long-term care., Competing Interests: LS holds shares of selenOmed GmbH, a company involved in Se status assessment. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Turan, Klein, Graf, Chillon, Plock and Schomburg.)

Background: Selenoproteins regulate pathways controlling neurodevelopment, e.g., redox signaling and thyroid hormone metabolism. However, studies investigating maternal selenium in relation to child neurodevelopmental disorders are scarce., Methods: 719 mother-child pairs from the prospective population-based Odense Child Cohort study in Denmark were included. Three selenium biomarkers, i.e. concentrations of serum selenium, selenoprotein P (SELENOP), and activity of glutathione peroxidase 3 (GPX3), along with serum copper, zinc and iron were measured in early third trimester (at 28.9+/-0.8 weeks of pregnancy). ADHD and ASD traits in children were assessed systematically using the established Child Behaviour Checklist at 5 years of age, based on a Danish reference cohort with cut-off at 90th percentile. Multivariable regression models adjusted for biologically relevant confounders were applied., Results: 155 of 719 (21.6 %) children had ASD traits and 59 of 719 (8.2 %) children had traits of ADHD at 5 years of age. In crude and adjusted models, all three selenium biomarkers associated inversely with ADHD traits. For ADHD, fully adjusted OR for 10 μg/L increment in selenium was 0.76 (95 % CI 0.60, 0.94), for one mg/L increment in SELENOP was 0.73 (0.56, 0.95), and for 10 U/L increment in GPx3 was 0.93 (0.87,1.00). Maternal total selenium was inversely associated with child ASD traits, OR per 10 μg/L increment was 0.85 (0.74, 0,98). SELENOP and GPx3 were not associated with ASD traits. The associations were specific to selenium, as other trace elements such as copper, zinc, or iron were not associated with the outcomes., Conclusions: The results provide coherent evidence for selenium deficiency as a risk factor for ADHD and ASD traits in an environment with borderline supply, the causality of which should be elucidated in a randomized controlled trial., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Ghrelin is an orexigenic peptide that becomes post-translationally modified. Natural autoantibodies to ghrelin (ghrelin-aAb) have been described in healthy subjects, in eating disorders and rheumatic diseases, with potential clinical relevance. Despite these important reports, the data base on the prevalence and physiological role is small and technical approaches for assessing ghrelin-aAb are few, encouraging respective research for improving knowledge on the potential endocrine significance., Methods: A novel immunoprecipitation assay was generated based on a fusion protein of human ghrelin with a reporter gene. Assay quality was verified with commercial antibodies. Assay characteristics and matrix effects were determined, including stability of natural ghrelin-aAb to freezing, signal linearity in dilution experiments, and comparison of different matrices. Three groups of serum samples were analyzed for ghrelin-aAb, comprising commercial sera from healthy subjects and patients with type 1 or type 2 diabetes mellitus., Results: The newly generated ghrelin-aAb assay proved sensitive, robust and reliable over a broad concentration range. Results from serum and plasma differed slightly. The signals from serum remained stable towards freezing and thawing, and in dilution experiments. Applying a mathematical criterion for outliers (P75 + 1.5-times IQR), an average prevalence of 11%-12% of positive samples was identified in the different human cohorts, with no significant sex-or disease-related difference., General Significance: A novel diagnostic autoantibody assay detected ghrelin-aAb with a similar prevalence in diabetic patients and controls, suggesting that autoimmunity to ghrelin plays little role in diabetes mellitus, but may be of relevance in other diseases where ghrelin signaling is essential., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Kasim, Chillon, Eleftheriadou, Rijntjes, Minich, Zechmann and Schomburg.)

Background: The essential trace element copper is relevant for many important physiological processes. Changes in copper homeostasis can result from disease and affect human health. A reliable assessment of copper status by suitable biomarkers may enable fast detection of subtle changes in copper metabolism. To this end, additional biomarkers besides serum copper and ceruloplasmin (CP) concentrations are required., Objectives: The aim of this study was to investigate the emerging copper biomarkers CP oxidase (CPO) activity, exchangeable copper (CuEXC) and labile copper in serum of healthy women and compare them with the conventional biomarkers total serum copper and CP., Method and Main Findings: This observational study determined CPO activity, the non CP-bound copper species CuEXC and labile copper, total serum copper and CP in sera of 110 healthy women. Samples were collected at four time points over a period of 24 weeks. The concentrations of total serum copper and CP were within the reference ranges. The comparison of all five biomarkers provided insight into their relationship, the intra- and inter-individual variability as well as the age dependence. The correlation and Principal Component Analyses (PCA) indicated that CP, CPO activity and total copper correlated well, followed by CuEXC, while the labile copper pool was unrelated to the other parameters., Conclusions: This study suggests that the non-CP-bound copper species represent copper pools that are differently regulated from total copper or CP-bound copper, making them interesting complementary biomarkers to enable a more complete assessment of body copper status with potential relevance for clinical application., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Selenium (Se) is an essential trace element for human health, but its nutritional supply is insufficient in large parts of the world. Mushrooms can be enriched in selenium and can serve as alternative and natural source of selenium supplementation. In the present study, two common mushroom species (Pleurotus ostreatus and Ganoderma lucidum), were enriched with two selenium compounds (selenite and selenate) to test their suitability as natural sources of selenium supplementation. Sharp differences in the the metabolic patterns of the fortified selenium were observed. Selenium was effectively metabolized in P. ostreatus but remained in inorganic form in G. lucidum. However, mushrooms extracts were effective in enhancing selenoprotein expression in cell lines. The present study highlights the importance of employing selenium speciation analysis with an element-selective technique to examine the metabolic products following mushroom fortification for nutritional purposes due to the different toxicological profile and bioavailability of different selenium biotransformation products., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

There is a dearth of data on Se status in very old adults. The aims of this study were to assess Se status and its determinants in 85-year-olds living in the Northeast of England by measuring serum Se and selenoprotein P (SELENOP) concentrations and glutathione peroxidase 3 (GPx3) activity. A secondary aim was to examine the interrelationships between each of the biomarkers. In total, 757 participants (463 women, 293 men) from the Newcastle 85+ Study were included. Biomarker concentrations were compared with selected cut-offs (serum Se: suboptimal 70 µg/l and deficient 45 µg/l; SELENOP: suboptimal 4·5 mg/l and deficient 2·6 mg/l). Determinants were assessed using linear regressions, and interrelationships were assessed using restricted cubic splines. Median (inter-quartile range) concentrations of serum Se, SELENOP and of GPx3 activity were 53·6 (23·6) µg/l, 2·9 (1·9) mg/l and 142·1 (50·7) U/l, respectively. Eighty-two percentage and 83 % of participants had suboptimal serum Se (< 70 µg/l) and SELENOP (< 4·5 mg/l), and 31 % and 40 % of participants had deficient serum Se (< 45 µg/l) and SELENOP (< 2·6 mg/l), respectively. Protein intake was a significant determinant of Se status. Additional determinants of serum Se were sex, waist:hip ratio, self-rated health and disease, while sex, BMI and physical activity were determinants of GPx3 activity. There was a linear association between serum Se and SELENOP, and nonlinear associations between serum Se and GPx3 activity and between SELENOP and GPx3 activity. These findings indicate that most participants had suboptimal Se status to saturate circulating SELENOP.

Purpose: We investigated whether selenium supplementation improves quality-of-life (QoL) in patients with autoimmune thyroiditis (ID:NCT02013479)., Methods: We included 412 patients ≥18 years with serum thyroid peroxidase antibody (TPOAb) level ≥100 IU/mL in a multicentre double-blinded randomised clinical trial. The patients were allocated 1:1 to daily supplementation with either 200 μg selenium as selenium-enriched yeast or matching placebo tablets for 12 months, as add-on to levothyroxine (LT4) treatment. QoL, assessed by the Thyroid-related Patient-Reported-Outcome questionnaire (ThyPRO-39), was measured at baseline, after six weeks, three, six, 12, and 18 months., Results: In total, 332 patients (81%) completed the intervention period, of whom 82% were women. Although QoL improved during the trial, no difference in any of the ThyPRO-39 scales was found between the selenium group and the placebo group after 12 months of intervention. In addition, employing linear mixed model regression no difference between the two groups was observed in the ThyPRO-39 composite score (28.8 [95%CI:24.5-33.6] and 28.0 [24.5-33.1], respectively; P=0.602). Stratifying the patients according to duration of the disease at inclusion, ThyPRO-39 composite score, TPOAb level, or selenium status at baseline did not significantly change the results. TPOAb levels after 12 months of intervention were lower in the selenium group than in the placebo group (1995 [95%CI:1512-2512] vs. 2344 kIU/L [1862-2951]; P=0.016) but did not influence LT4 dosage or free triiodothyronine/free thyroxin ratio., Conclusion: In hypothyroid patients on LT4 therapy due to autoimmune thyroiditis, daily supplementation with 200 μg selenium or placebo for 12 months improved QoL to the same extent.

Background: Recent data from the randomized SUSTAIN CSX trial could not confirm clinical benefits from perioperative selenium treatment in high-risk cardiac surgery patients. Underlying reasons may involve inadequate biosynthesis of glutathione peroxidase (GPx3), which is a key mediator of selenium's antioxidant effects. This secondary analysis aimed to identify patients with an increase in GPx3 activity following selenium treatment. We hypothesize that these responders might benefit from perioperative selenium treatment., Methods: Patients were selected based on the availability of selenium biomarker information. Four subgroups were defined according to the patient's baseline status, including those with normal kidney function, reduced kidney function, selenium deficiency, and submaximal GPx3 activity., Results: Two hundred and forty-four patients were included in this analysis. Overall, higher serum concentrations of selenium, selenoprotein P (SELENOP) and GPx3 were correlated with less organ injury. GPx3 activity at baseline was predictive of 6-month survival (AUC 0.73; p = 0.03). While selenium treatment elevated serum selenium and SELENOP concentrations but not GPx3 activity in the full patient cohort, subgroup analyses revealed that GPx3 activity increased in patients with reduced kidney function, selenium deficiency and low to moderate GPx3 activity. Clinical outcomes did not vary between selenium treatment and placebo in any of these subgroups, though the study was not powered to conclusively detect differences in outcomes., Conclusions: The identification of GPx3 responders encourages further refined investigations into the treatment effects of selenium in high-risk cardiac surgery patients., (© 2023. The Author(s).)

Background: Diet is an important modifiable risk factor for gestational diabetes mellitus (GDM) and its related complications; however, the role of essential micronutrients such as selenium (Se), particularly in populations with low Se intake, is inconclusive., Objectives: The aim was to investigate the association of 3 established biomarkers of Se status with GDM, gestational glucose metabolism, and large for gestational-age offspring., Methods: This study included 1346 pregnant females with 2294 serum samples from the prospective, population-based Odense Child Cohort study, Denmark. Serum Se, selenoprotein P (SELENOP) concentrations, and glutathione peroxidase 3 (GPX3) activity were measured in early and late pregnancy, and fasting glucose and insulin assessments in late pregnancy. Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was calculated, and the GDM definition was according to the WHO 2013 threshold of fasting venous plasma glucose of ≥5.1 mmol/L. A subcohort underwent an oral glucose tolerance test. Regression models adjusted for various confounders quantified dose-dependent associations., Results: Se and SELENOP declined during pregnancy. There were dose-dependent inverse associations of early GPX3 with late pregnancy GDM (WHO 2013), fasting glucose, insulin, HOMA-IR, and 2 h glucose. The odds ratio (OR) of GDM was 0.33 (95% CI: 0.16, 0.65) for 1 log-scale-increment in early GPX3 activity. Late pregnancy GPX3 and SELENOP were inversely associated with GDM and HOMA-IR; the OR of GDM was 0.21 (95% CI: 0.12, 0.38) and 0.52 (95% CI: 0.35, 0.77), for 1 log-scale-increment of GPX3 and SELENOP, respectively. A decline in Se biomarkers during pregnancy was associated with a higher risk of GDM and higher HOMA-IR. Low GPX3 activity in late pregnancy was associated with a higher risk of large for gestational-age offspring, partly (∼20%) mediated by fasting glucose concentrations (P = 0.006)., Conclusions: Low serum Se in pregnancy, particularly GPX3 activity, is independently associated with risk of GDM and large for gestational age. Offering Se status assessment in pregnancy identifies females at high risk for GDM who may benefit from Se substitution., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

The essential trace elements copper, selenium and zinc are of relevance for immunity and immune response to vaccination. In this longitudinal study, adult healthcare workers (n = 126) received two doses of an mRNA vaccine (BNT162b2), and longitudinal serum samples were prepared. Vaccine-induced antibodies and their neutralizing activity were analyzed, and the trace elements copper, zinc, and selenium along with the copper transporter ceruloplasmin were measured. Subjects with combined deficiency of copper and zinc, i.e. both in the lowest tertiles at baseline, displayed particularly low antibody titers at three (Double Q1: 13 AU/mL vs. not double Q1: 29 AU/mL) and six (Double Q1: 200 AU/mL vs. not double Q1: 425 AU/mL) weeks after vaccination (p < 0.05). The results indicate the potential importance of an adequate trace element status of copper and zinc for raising a strong vaccine-induced SARS-CoV-2 antibody response, and highlights the importance of considering combined micronutrient insufficiencies, as single deficiencies may synergize., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:L.S. hold shares of selenOmed GmbH, a company involved in Se status assessment.There are no other activities or relationships that may have influenced the submitted work., (© 2023 The Authors. Published by Elsevier Ltd.)

Introduction: Low serum selenium and altered tumour RNA expression of certain selenoproteins are associated with a poor breast cancer prognosis. Selenoprotein expression stringently depends on selenium availability, hence circulating selenium may interact with tumour selenoprotein expression. However, there is no matched analysis to date., Methods: This study included 1453 patients with newly diagnosed breast cancer from the multicentric prospective Sweden Cancerome Analysis Network - Breast study. Total serum selenium, selenoprotein P and glutathione peroxidase 3 were analysed at time of diagnosis. Bulk RNA-sequencing was conducted in matched tumour tissues. Fully adjusted Cox regression models with an interaction term were employed to detect dose-dependent interactions of circulating selenium with the associations of tumour selenoprotein mRNA expression and mortality., Results: 237 deaths were recorded within ~ 9 years follow-up. All three serum selenium biomarkers correlated positively (p < 0.001). All selenoproteins except for GPX6 were expressed in tumour tissues. Single cell RNA-sequencing revealed a heterogeneous expression pattern in the tumour microenvironment. Circulating selenium correlated positively with tumour SELENOW and SELENON expression (p < 0.001). In fully adjusted models, the associations of DIO1, DIO3 and SELENOM with mortality were dose-dependently modified by serum selenium (p < 0.001, p = 0.020, p = 0.038, respectively). With increasing selenium, DIO1 and SELENOM associated with lower, whereas DIO3 expression associated with higher mortality. Association of DIO1 with lower mortality was only apparent in patients with high selenium [above median (70.36 µg/L)], and the HR (95%CI) for one-unit increase in log(FPKM + 1) was 0.70 (0.50-0.98)., Conclusions: This first unbiased analysis of serum selenium with the breast cancer selenotranscriptome identified an effect-modification of selenium on the associations of DIO1, SELENOM, and DIO3 with prognosis. Selenium substitution in patients with DIO1-expressing tumours merits consideration to improve survival., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The aim of this study was to compare the iron and calcium status in singleton and twin pregnancies and to assess whether there is an increased risk for iron and calcium deficiency in twin gestation. The study included 105 singleton and 9 twin pregnancies at or above 35 weeks of gestation. Information on prenatal supplementation with iron or calcium was acquired, and adverse perinatal outcomes were recorded. Biosamples from all 114 mothers and 73 newborns (61 singleton and 12 twin newborns) were finally analyzed. Total iron and calcium concentrations in serum were measured through total reflection X-ray fluorescence analysis. The results indicated no significant differences in maternal serum iron and calcium concentrations between singleton and twin pregnancies. Similarly, iron and calcium concentrations in newborn umbilical cord serum samples were not different between singleton and twin pregnancies. The comparison of total iron and calcium between mothers and umbilical cord serum indicated significantly lower concentrations in the mothers, with the differences being not homogenous but rather pair-specific. A significant positive correlation between maternal serum and umbilical cord serum calcium concentration was noticed. Prenatal iron supplementation was associated with higher iron concentrations in both mothers and newborns, supporting the efficiency of supplementation and the quality of the study methods. Collectively, the data indicate no significant differences in serum iron and calcium concentrations with regard to singleton or twin pregnancies and the efficiency of iron supplementation during pregnancy for increasing iron status.

Chronic Fatigue Syndrome (CFS) presents with symptoms of hypothyroidism, including mental and physical fatigue, poor sleep, depression, and anxiety. However, thyroid hormone (TH) profiles of elevated thyrotropin and low thyroxine (T4) are not consistently observed. Recently, autoantibodies to the Se transporter SELENOP (SELENOP-aAb) have been identified in Hashimoto's thyroiditis and shown to impair selenoprotein expression. We hypothesized that SELENOP-aAb are prevalent in CFS, and associate with reduced selenoprotein expression and impaired TH deiodination. Se status and SELENOP-aAb prevalence was compared by combining European CFS patients (n = 167) and healthy controls (n = 545) from different sources. The biomarkers total Se, glutathione peroxidase (GPx3) and SELENOP showed linear correlations across the samples without reaching saturation, indicative of Se deficiency. SELENOP-aAb prevalence was 9.6-15.6% in CFS versus 0.9-2.0% in controls, depending on cut-off for positivity. The linear correlation between Se and GPx3 activity was absent in SELENOP-aAb positive patients, suggesting impaired Se supply of kidney. A subgroup of paired control (n = 119) and CSF (n = 111) patients had been characterized for TH and biochemical parameters before. Within this subgroup, SELENOP-aAb positive patients displayed particularly low deiodinase activity (SPINA-GD index), free T3 levels, total T3 to total T4 (TT3/TT4) and free T3 to free T4 (FT3/FT4) ratios. In 24 h urine, iodine concentrations were significantly lower in SELENOP-aAb positive than in SELENOP-aAb negative patients or controls (median (IQR); 43.2 (16.0) vs. 58.9 (45.2) vs. 89.0 (54.9) μg/L). The data indicate that SELENOP-aAb associate with low deiodination rate and reduced activation of TH to active T3. We conclude that a subset of CFS patients express SELENOP-aAb that disturb Se transport and reduce selenoprotein expression in target tissues. Hereby, TH activation decreases as an acquired condition not reflected by thyrotropin and T4 in blood. This hypothesis opens new diagnostic and therapeutic options for SELENOP-aAb positive CFS, but requires clinical evidence from intervention trials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. LS and PS hold shares of selenOmed GmbH, a company involved in Se status assessment. PS and QS are employees of selenOmed GmbH. LS is listed as inventor on a related patent application. No other relationships or activities are known that could appear to have influenced the submitted work., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Selenium is essential for expression and proper function of a set of redox active selenoproteins implicated in aging-relevant diseases, e.g. type 2 diabetes mellitus (T2D) and hypertension. However, data in cohorts of older adults, particularly with respect to different Se biomarkers and sex-specific analyses are sparse., Objective: To assess associations of serum Se and selenoprotein P (SELENOP) concentrations with T2D and hypertension in a cohort of older females and males., Methods: This study included 1500 participants from the Berlin Aging Study II. Diagnosis of T2D was made in case of antidiabetic medication, self-reported T2D, or laboratory parameters. Diagnosis of hypertension was based on self-report, blood pressure measurement, or anti-hypertensive medication. Se was measured by spectroscopy, and SELENOP by ELISA. Multiple adjusted regression models quantified dose-dependent associations., Results: Participants had a median(IQR) age of 68 (65,71) years, and 767 (51%) were women. 191 (13%) participants had T2D and 1126 (75%) had hypertension. Se and SELENOP correlated significantly (r = 0.59, p < 0.001), and were elevated in those with self-reported Se supplementation. Serum Se and SELENOP were not associated with T2D in the whole cohort. In men, SELENOP was positively associated with T2D, OR (95%CI) for one mg/L increase in SELENOP was 1.22 (1.00,1.48). Se was non-linearly associated with hypertension, comparing to the lowest quartile (Q1), and participants with higher Se levels (Q3) had a lower OR (95%CI) of 0.66 (0.45,0.96), which was specific for men. SELENOP positively associated with hypertension, and OR (95%CI) per one mg/L increase was 1.15 (1.01,1.32)., Conclusions: The data suggest a sex-specific interrelationship of Se status with T2D and hypertension, with apparent biomarker-specific associations., Competing Interests: Declaration of competing interest LS holds shares of selenOmed GmbH, a company involved in Se status assessment; no other relationships or activities that could appear to have influenced the submitted work are indicated., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

There is a public concern that COVID-19 vaccination and SARS-CoV-2 antibodies (Abs) negatively affect male fertility. However, the evidence for the presence of SARS-CoV-2 Abs in seminal plasma (SP) is lacking. We examined whether Abs were detectable in SP after COVID-19 vaccination in 86 men using a direct Ab measurement and by quantification of their neutralizing activity. The results show the presence of SARS-CoV-2 Abs in SP, with a strong correlation to the serum Abs, increasing with the number of vaccinations. Furthermore, the Ab titers are correlating with the neutralization activity. The SARS-CoV-2 vaccination parameters showed no association with the markers of sperm quality. In conclusion, this study indicates substantial levels of Abs in SP after COVID-19 vaccination that correlate with serum Ab titers but do not associate with sperm quality., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Known hereditary human diseases featuring impaired copper trafficking across cellular membranes involve ATP7A (Menkes disease, occipital horn disease, X-linked spinal muscular atrophy type 3) and ATP7B (Wilson disease). Herein, we report a newborn infant of consanguineous parents with a homozygous pathogenic variant in a highly conserved sequence of SLC31A1, coding for the copper influx transporter 1, CTR1. This missense variant, c.236T > C, was detected by whole exome sequencing. The infant was born with pulmonary hypoplasia and suffered from severe respiratory distress immediately after birth, necessitating aggressive mechanical ventilation. At 2 weeks of age, multifocal brain hemorrhages were diagnosed by cerebral ultrasound and magnetic resonance imaging, together with increased tortuosity of cerebral arteries. Ensuing seizures were only partly controlled by antiepileptic drugs, and the infant became progressively comatose. Laboratory investigations revealed very low serum concentrations of copper and ceruloplasmin. No hair shaft abnormalities were detected by dermatoscopy or light microscopic analyses of embedded hair shafts obtained at 4 weeks of life. The infant died after redirection of care and elective cessation of invasive mechanical ventilation at 1 month of age. This case adds SLC31A1 to the genes implicated in severe hereditary disorders of copper transport in humans., (© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Introduction: Every second woman suffering from infertility asks for medical help. There is public concern that vaccination-induced antibodies (Ab) are negatively associated with fertility. A recent study has demonstrated an association between SARS-CoV-2 vaccination and a lower pregnancy rate in the subsequent 60 days. Consequently, Ab could affect fertility success in assisted reproduction., Methods: To address this question, we compared fertilization outcomes of vaccinated (n=35) and nonvaccinated (n=34) women. Paired serum samples and multiple follicular fluids (FF) (up to 10 from the same donor) were collected during the course of assisted reproduction and characterized for oocyte quality, the presence of Ab and trace element concentrations., Results: The results showed a positive correlation of vaccination-induced neutralizing activity of SARS-CoV-2-Ab in serum and FF. On average, Ab concentrations in serum were higher than in the corresponding FF. However, wide variations in SARS-CoV-2 Ab titers were observed between different FF, correlating to trace element levels, even when retrieved from the same donor., Discussion: Overall, FF contents are highly variable, but no negative association was observed between Ab in serum or FF and fertilization success and oocyte development, supporting the safety of SARS-CoV-2 vaccination during assisted reproduction., Competing Interests: Authors GW and MS were employed by Das Kinderwunsch Institut Schenk GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chillon, Weiss, Demircan, Minich, Schenk and Schomburg.)

Introduction: Selenium (Se) is an essential trace element that exerts its effects mainly as the proteinogenic amino acid selenocysteine within a small set of selenoproteins. Among all family members, selenoprotein P (SELENOP) constitutes a particularly interesting protein as it serves as a biomarker and serum Se transporter from liver to privileged tissues. SELENOP expression is tightly regulated by dietary Se intake, inflammation, hypoxia and certain substances, but a systematic drug screening has hitherto not been performed., Methods: A compound library of 1861 FDA approved clinically relevant drugs was systematically screened for interfering effects on SELENOP expression in HepG2 cells using a validated ELISA method. Dilution experiments were conducted to characterize dose-responses. A most potent SELENOP inhibitor was further characterized by RNA-seq analysis to assess effect-associated biochemical pathways., Results: Applying a 2-fold change threshold, 236 modulators of SELENOP expression were identified. All initial hits were replicated as biological triplicates and analyzed for effects on cell viability. A set of 38 drugs suppressed SELENOP expression more than three-fold, among which were cancer drugs, immunosuppressants, anti-infectious drugs, nutritional supplements and others. Considering a 90% cell viability threshold, resveratrol, vidofludimus, and antimony potassium-tartrate were the most potent substances with suppressive effects on extracellular SELENOP concentrations. Resveratrol suppressed SELENOP levels dose-dependently in a concentration range from 0.8 μM to 50.0 μM, without affecting cell viability, along with strong effects on key genes controlling metabolic pathways and vesicle trafficking., Conclusion: The results highlight an unexpected direct effect of the plant stilbenoid resveratrol, known for its antioxidative and health-promoting effects, on the central Se transport protein. The suppressive effects on SELENOP may increase liver Se levels and intracellular selenoprotein expression, thereby conferring additional protection to hepatocytes at the expense of systemic Se transport. Further physiological effects from this interaction require analyses in vivo and by clinical studies., Competing Interests: Declaration of competing interest L.S. holds shares of selenOmed GmbH, a company involved in Se status assessment. The other authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Certain trace elements are essential for life and affect immune system function, and their intake varies by region and population. Alterations in serum Se, Zn and Cu have been associated with COVID-19 mortality risk. We tested the hypothesis that a disease-specific decline occurs and correlates with mortality risk in different countries in Europe., Methods: Serum samples from 551 COVID-19 patients (including 87 non-survivors) who had participated in observational studies in Europe (Belgium, France, Germany, Ireland, Italy, and Poland) were analyzed for trace elements by total reflection X-ray fluorescence. A subset (n=2069) of the European EPIC study served as reference. Analyses were performed blinded to clinical data in one analytical laboratory., Results: Median levels of Se and Zn were lower than in EPIC, except for Zn in Italy. Non-survivors consistently had lower Se and Zn concentrations than survivors and displayed an elevated Cu/Zn ratio. Restricted cubic spline regression models revealed an inverse nonlinear association between Se or Zn and death, and a positive association between Cu/Zn ratio and death. With respect to patient age and sex, Se showed the highest predictive value for death (AUC=0.816), compared with Zn (0.782) or Cu (0.769)., Discussion: The data support the potential relevance of a decrease in serum Se and Zn for survival in COVID-19 across Europe. The observational study design cannot account for residual confounding and reverse causation, but supports the need for intervention trials in COVID-19 patients with severe Se and Zn deficiency to test the potential benefit of correcting their deficits for survival and convalescence., Competing Interests: LS holds shares of selenOmed GmbH, a company involved in selenium status assessment. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Demircan, Chillon, Bracken, Bulgarelli, Campi, Du Laing, Fafi-Kremer, Fugazzola, Garcia, Heller, Hughes, Ide, Klingenberg, Komarnicki, Krasinski, Lescure, Mallon, Moghaddam, Persani, Petrovic, Ruchala, Solis, Vandekerckhove and Schomburg.)

The demand for selenium (Se) increases during pregnancy since this element supports child growth, proper neuronal development and maternal thyroid function. The issue is particularly relevant for populations living in areas with a limited selenium supply, where many pregnant women opt for Se supplementation. The efficiency of this measure is unknown, although it seems vital in the prevention of severe Se deficiency. In order to evaluate this hypothesis, an observational study was conducted in Poland, where Se deficiency is prevalent. Pregnant women were invited to participate in the study and provided serum samples at the end of pregnancy ( n = 115). Information on the supplemental intake of micronutrients was recorded in a face-to-face interview. In addition, serum samples were isolated from the cord blood of newborns at delivery ( n = 112) and included in the analyses. Thyroid hormone status was evaluated by routine laboratory tests, and Se status was determined by total Se and selenoprotein P (SELENOP) concentrations and extracellular glutathione peroxidase (GPX3) activity. The three parameters of Se status correlated strongly within the group of mothers and within the group of newborns, with an additional significant correlation found among mother-child pairs. One-third of mothers reported additional Se intake, mainly as a component of multi-micronutrient supplements, at a mean (±SD) dosage of 42 ± 14 µg Se/day. Despite this regime, most of the women presented an insufficient Se status, with 79% of mothers displaying serum Se concentrations below 70 µg/L (indicating Se deficiency) and 22% showing levels below 45.9 µg/L (severe Se deficiency). The inadequate Se supply was also reflected in relatively low SELENOP concentrations and GPX3 activity. Neither total Se nor SELENOP or GPX3 levels were significantly higher in the group of mothers reporting the intake of supplements than in the non-supplementing group. Nevertheless, elevated SELENOP concentrations were observed in the subgroup receiving supplements with more than 55 µg/day. We conclude that the self-administered supplementation of small Se dosages was not sufficient to achieve replete Se status in the micronutrient scant area. However, the maternal Se deficit measured by either Se, SELENOP or GPX3 was transferred from mothers to the newborns, as the parameters correlated strongly in the mother-newborn pairs of samples. It is vital to re-evaluate the guidelines concerning pregnancy care and monitoring of micronutrient status during pregnancy, in particular in areas where deficiencies are present.

Background: Zinc (Zn) is an essential trace element with high relevance for the immune system, and its deficiency is associated with elevated infection risk and severe disease course. The association of Zn status with the immune response to SARS-CoV-2 vaccination is unknown., Methods: A cohort of adult health care workers (n=126) received two doses of BNT162B2, and provided up to four serum samples over a time course of 6 months. Total SARS-CoV-2 IgG and neutralizing antibody potency was determined, along with total as well as free Zn concentrations., Results: The SARS-CoV-2 antibodies showed the expected rise in response to vaccination, and decreased toward the last sampling point, with highest levels measured three weeks after the second dose. Total serum Zn concentrations were relatively stable over time, and showed no significant association with SARS-CoV-2 antibodies. Baseline total serum Zn concentration and supplemental intake of Zn were both unrelated to the antibody response to SARS-CoV-2 vaccination. Time resolved analysis of free Zn indicated a similar dynamic as the humoral response. A positive correlation was observed between free Zn concentrations and both the induced antibodies and neutralizing antibody potency., Conclusion: While the biomarkers of Zn status and supplemental Zn intake appeared unrelated to the humoral immune response to SARS-CoV-2 vaccination, the observed correlation of free Zn to the induced antibodies indicates a diagnostic value of this novel biomarker for the immune system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chillon, Maares, Demircan, Hackler, Sun, Heller, Diegmann, Bachmann, Moghaddam, Haase and Schomburg.)

The essential trace element selenium (Se) is of central importance for human health and particularly for a regular functioning of the immune system. In the context of the current pandemic, Se deficiency in patients with COVID-19 correlated with disease severity and mortality risk. Selenium has been reported to be associated with the immune response following vaccination, but it is unknown whether this also applies to SARS-CoV-2 vaccines. In this observational study, adult health care workers (n = 126) who received two consecutive anti-SARS-CoV-2 vaccinations by BNT162b2 were followed for up to 24 weeks, with blood samples collected at the first and second dose and at three and 21 weeks after the second dose. Serum SARS-CoV-2 IgG titres, neutralising antibody potency, total Se and selenoprotein P concentrations, and glutathione peroxidase 3 activity were quantified. All three biomarkers of Se status were significantly correlated at all the time points, and participants who reported supplemental Se intake displayed higher Se concentrations. SARS-CoV-2 IgG titres and neutralising potency were highest three weeks after the second dose and decreased towards the last sampling point. The humoral immune response was not related to any of the three Se status biomarkers. Supplemental Se intake had no effect at any time point on the vaccination response as measured by serum SARS-CoV-2 IgG levels or neutralising potency. Overall, no association was found between Se status or supplemental Se intake and humoral immune response to COVID-19 mRNA vaccination., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

The immune response to vaccination with SARS-CoV-2 vaccines varies greatly from person to person. In addition to age, there is evidence that certain micronutrients influence the immune system, particularly vitamin D. Here, we analysed SARS-CoV-2 IgG and neutralisation potency along with 25-hydroxy-cholecalciferol [25(OH)D] concentrations in a cohort of healthy German adults from the time of vaccination over 24 weeks. Contrary to our expectations, no significant differences were found in the dynamic increase or decrease of SARS-CoV-2 IgG as a function of the 25(OH)D status. Furthermore, the response to the first or second vaccination, the maximum SARS-CoV-2 IgG concentrations achieved, and the decline in SARS-CoV-2 IgG concentrations over time were not related to 25(OH)D status. We conclude that the vaccination response, measured as SARS-CoV-2 IgG concentration, does not depend on 25(OH)D status in healthy adults with moderate vitamin D status.